Enantioselective formal (3 + 3) cycloaddition of bicyclobutanes with nitrones enabled by asymmetric Lewis acid catalysis

The absence of catalytic asymmetric methods for synthesizing chiral (hetero)bicyclo[n.1.1]alkanes has hindered their application in new drug discovery. Here we demonstrate the achievability of an asymmetric polar cycloaddition of bicyclo[1.1.0]butane using a chiral Lewis acid catalyst and a bidentate chelating bicyclo[1.1.0]butane substrate, as exemplified by the current enantioselective formal (3 + 3) cycloaddition of bicyclo[1.1.0]butanes with nitrones. In addition to the diverse bicyclo[1.1.0]butanes incorporating an acyl imidazole group or an acyl pyrazole moiety, a wide array of nitrones are compatible with this Lewis acid catalysis, successfully assembling two congested quaternary carbon centers and a chiral aza-trisubstituted carbon center in the pharmaceutically important hetero-bicyclo[3.1.1]heptane product with up to 99% yield and >99% ee.

The development of asymmetric catalytic reactions, as well as the introduction of new catalytic methods and strategies for preparing chiral molecules in enantioenriched forms, is crucial for drug discovery and innovation.This importance is underscored by the fact that over half of all pharmaceuticals currently in use are chiral compounds containing carbon stereocenters 1 .
In 2021, Baran and co-workers successfully achieved enantiopure BCP bioisosteres through SFC separation.Furthermore, their study revealed that substituting benzenoids with either Ror S-enantiomers of BCPs results in distinct drug bioactivities 36 .Consequently, the development of catalytic asymmetric synthesis techniques for (hetero) bicyclo[n.1.1]alkanesis not only highly desirable but would also significantly accelerate the creation of drugs with superior properties.While chirality transfer and bio-catalysis strategies have been used to synthesize chiral BCPs and BCHs respectively 37,38 , before the elegant asymmetric (3 + 2) cycloadditions of BCBs reported by Bach 39 and Jiang 40 , the only asymmetric difunctionalization reactions within the BCB framework were limited to ring opening processes 41,42 .Notably, the strategies employed by Bach 39 and Jiang 40 , focus exclusively on asymmetric photochemical cycloadditions of BCBs.Our group has recently achieved palladium-catalyzed enantioselective [2σ + 2σ] cycloadditions of BCBs with vinyl oxiranes to synthesize O-BCHeps (Fig. 1d) 43 .
Besides radical cycloadditions, polar cycloadditions of BCBs have been developed after Leitch's pioneering research in Lewis acid catalysis 44 .Currently, the Lewis acid catalyzed (3+n) polar cycloadditions of BCBs can utilize ketenes 45 , aldehydes 46 , heteroarenes 47,48 , dienol ethers 49 , ynamides 50 and imidazolidines 51 as the cycloaddition partners.During the preparation of this manuscript, Deng pioneered the Eu(OTf) 3 -catalyzed cycloadditions of BCBs with nitrones 29 .This innovation resulted in the creation of a range of structurally unique and biologically intriguing 2-oxa-3-aza-BCHep skeletons, which show promise as bioisosteres for pyridines.Despite significant progress in this area, the enantioselective synthesis of (hetero)bicyclo[n.1.1]alkanesthrough Lewis acid catalysis is still unexplored and poses a significant challenge.A major challenge in achieving the asymmetric Lewis acidcatalyzed (3 + 3) cycloadditions of BCBs is identifying optimal ligand capable of overcoming the significant racemic background reaction 29,52 , thus facilitating the formation of two congested carbon centers together with a chiral carbon center with high enantioselective control 53,54 .In contrast to donor-acceptor cyclopropanes [55][56][57][58][59][60][61][62][63] , which feature two chelating, electron-withdrawing groups to form a stable chiral catalyst-substrate complex, achieving catalytic asymmetric reactions of BCBs with only a single electron-withdrawing group, leading to chiral environments with variable conformation, poses greater challenges.To address these challenges, we investigated the utilization of BCBs with bidentate coordinating groups and a chiral Lewis acid catalysis strategy in the asymmetric (3 + 3) cycloaddition of BCBs (Fig. 1e).
Additionally, BCB with o-tolyl group (3hb) and naphthyl-substituted BCB (3ib) also efficiently produced the desired cycloadducts with excellent enantioselectivity.Notably, the BCB 1e, containing a highly electron-withdrawing trifluoromethyl group, was previously considered incompatible with Glorius's Lewis acid catalytic system 46 .However, it still yielded the corresponding cycloadducts (3eb versus 3bb) in good yield and selectivity.These results suggest that it follows the same pathway as Deng's work, involving a concerted nucleophilic ring-opening mechanism of BCBs with nitrones 29 .Subsequently, we investigated the impact of N-substitution of 2-acyl imidazole in the current cycloadditions.The identity of the N-substituent (3jb-mb) had a minor effect on enantioselectivity (98-99% ee), but did influence the yield (71-85% yield).Moreover, we found that the Glorius's BCB substrates with acyl pyrazole substituent instead of acyl imidazole could also be well accepted in the enantioselective cycloaddition with 2b, and the corresponding (3 + 3) cycloadducts were produced with up to 99% yield and >99% ee.However, in some cases, lower ee values were observed when using Glorius's BCB compared to BCBs featuring a 2-acyl imidazole moiety (3ob versus 3eb).For instance, the (3 + 3) reaction of 2n with N-phenyl nitrone 2d yields the desired 3nd with 28% ee (Supplementary Fig. 5).In contrast, the cycloaddition of 1a and 2d produces 3ad with 94% ee under identical reaction conditions.Unfortunately, the employment of the methyl-substituted BCB delivered the corresponding product with low ee (52% ee, Supplementary Fig. 5).

Synthetic applications
To demonstrate the synthetic utility of these chiral cycloadducts, several transformations of the cycloadducts were investigated (Fig. 4).The cycloaddition of 1n and 2b is scalable to 1.0 mmol under standard reaction conditions, yielding 3nb with 99% yield and 99% ee.The acyl pyrazole moiety of 3nb and 3qb was converted to an aldehyde group using LiAlH 4 , preserving its chirality (Fig. 4a).Moreover, in a two-step process, we integrated the chiral 2-oxa-3-azaBCHep 3qb unit into the structures of the antidyskinesia agent Sarizotan 68 and dopamine D 2 receptor antagonist Adoprazine 69 by substituting the pyridine ring.These instances showcased the practical synthetic value of the chiral (3 + 3) cycloadducts.Cleavage of the imidazole moiety gave rise to the desired ketone 5 in 75% yield.The nucleophilic substitution or addition of 3nb smoothly produce enantiomerically enriched compounds 6 and 7, respectively.Cleaving the N-O bond in 3nb and deprotecting the benzyl group in the presence of H 2 and Pd(OH) 2 /C produces functionalized cyclobutane 8 (Fig. 4b).Notably, including a terminal-alkyne group in cycloadduct 3as facilitates the incorporation of the chiral hetero-BCHep scaffold into bioactive compounds like Adapalene and Isoxepac through click reaction (Fig. 4c).

Mechanistic studies
In order to gain insight into this transformation, a study was conducted to examine the correlation between the ee value of PyIPI-L10 and that of (S)-3ab (Fig. 5a).The study revealed a linear relationship, suggesting that an active catalyst/ligand being of a monomeric nature.Based on Deng 29 and Xie&Guo's work 66,67 , to unravel the origin of enantiocontrol, density functional theory (DFT) calculations were performed at PBE0/6-31 G(d)-SDD level of theory, using 1a and 2b as the model substrates along with the Co(II) − L12 chiral system.As shown in Fig. 5b, transition states Ts-S and Ts-R leading to both products were located, in which divalent Co coordinated with two nitrogen and one oxygen atoms of L12 as well as one oxygen and nitrogen atoms of 1a, generating a square pyramidal geometry.The difference between the two activation barriers of the intramolecular nucleophilic cyclization for the two enantiomers was 2.2 kcal/mol, consistent with the excellent enantioselectivity experimentally observed.Moreover, noncovalent interactions between reactant fragment and L12 in Ts-S and Ts-R were explored using independent gradient model based on Hirshfeld partition (IGMH) analysis 70 .Three pairs of C-H•••O interaction existed in both Ts-S and Ts-R.Notably, in the favored transition state Ts-S, imidazolidone of L12 engaged in C-H…π interaction with phenyl group of nitrone 2a, likely dominating the preference for the nucleophilic attack of the enolate on the Re-face of nitrone 2a to furnish the (S)-configuration of product 3ab.

Discussion
In

Methods
General Procedure for the Enantioselective (3 + 3) Cycloadditions Under an atmosphere of N 2 , to a 25 mL oven-dried Schlenk tube were added Co(OTf) 2 (7.1 mg, 0.020 mmol) and L10 (17.1 mg, 0.024 mmol), followed by 2.0 mL of anhydrous CH 2 Cl 2 .The solution was stirred at 25 °C for 0.5 h, and then the BCBs 1 (0.20 mmol, 1.0 equiv) and nitrones 2 (0.24 mmol, 1.2 equiv) were added.Then the resulting mixture was stirred at room temperature for 16 h till full conversion of 1 by TLC analysis.After the solvent was removed under reduced pressure, the residue was directly subjected to a column chromatography

Data availability
The data supporting the findings of this study are available within this article and its Supplementary Information, which contains experimental details, characterization data, copies of NMR spectra and HPLC spectra for all new compounds, X-ray structural analysis, and DFT calculation data.Crystallographic data for the structures reported in this article have been deposited at the Cambridge Crystallographic Data Centre, under deposition numbers CCDC 2345666 ((S)-3ao).
Copies of the data can be obtained free of charge via https://www.ccdc.cam.ac.uk/structures/.Source data of DFT calculation are also provided with this paper.All other data are available from the corresponding author upon request.Source data are provided with this paper.Open

Fig. 4 |
Fig. 4 | Scale-up and derivatizations.a Scale-up synthesis of 3nb.b Derivatization of the cycloadducts.c Late-stage modification of drugs.

Fig. 5 |
Fig. 5 | Non-linear effect study and DFT calculations.a The relationship between ee values of ligand L10 and product 3ab.b Optimized structures of the enantiodetermining transition state and IGMH analysis of the non-covalent interactions in Ts-S and Ts-R.The Gaussian 09 level of PBE0/6-31 G(d)-SDD was used.All distances are in angstrom.The relative free energies are in kcal mol −1 .

Table 1 |
Optimization of the reaction conditions a Lewis acid (10 mol%) and ligand (12 mol%) in CH 2 Cl 2 at room temperature for 24 h.b 2a was used.cNMRyield with CH 2 Br 2 as an internal standard.dTheenantiomeric excess (ee) of the product was determined by HPLC using a chiral stationary phase.
conclusion, a strategy utilizing Lewis acid catalysis has been developed for the atom-economic and enantioselective synthesis of bridged bicyclic scaffolds from BCBs.By utilizing a chiral Co(II)/PyIPI catalyst and bidentate chelating BCB substrates, we can efficiently access enantioenriched pharmaceutically important hetero-bicyclo[3.1.1]heptane derivatives by varying the BCBs or nitrones used in the (3 + 3) cycloadditions.The acyl imidazole group or acyl pyrazole moiety in BCBs plays a crucial role in stereocontrol.The synthetic utility of this protocol has been further demonstrated in the concise synthesis of the analog of bioactive pyridine and the late-stage functionalization of drugs.Given the significance of chiral (hetero)bicyclo[n.1.1]alkanescaffolds as bioisosteres and the need for a new strategy for the asymmetric cycloaddition of BCBs, we anticipate that this approach will yield positive outcomes in both synthetic and medicinal chemistry.
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